The v-erb A oncogene potentiates erythroid transformation and alters the growth properties of fibroblasts. V-erb A is a virus transduced, aberrant copy of a gene for a thyroid hormone receptor. Thyroid hormone receptors (TRs) are ligand-regulated transcription factors, and belong to a larger family of nuclear receptors that play crucial roles in metazoan homeostasis, differentiation, and neoplasia. The v-Erb A protein acts as a transcriptional repressor, inhibiting expression of genes normally activated by TRs and by the closely related retinoic acid receptors (RARs). Therefore, v-erb A has been proposed as a prototype of a novel class of oncogene, acting in cancer as a dominant-negative allele. Similar dominant-negative mutants of nuclear receptors, such as PML-RAR, play important roles in human endocrine disease and cancers. We wish to understand the mechanism of action of the v-erb A oncogene, to relate its role in viral neoplasia to events in normal differentiation, and to use v-erb A as a model to provide new insights into human diseases. A. We will identify v-Erb A and PML-RAR target genes. B. We will determine how v-Erb A represses target gene expression once bound to a target DNA. C. We will determine how v-Erb A function is altered by other signal transduction pathways operative in the erythroleukemic cell. D. V-Erb A will be used as a model to improve our understanding of the actions of the aberrant nuclear receptors involved in human disease. Due to its derivation from a nuclear hormone receptor, v-erb A is one of the most experimentally accessible oncogenes, and holds unusual potential for understanding both neoplasia and the actions of nuclear hormone receptors in the normal organism.